Upper airway viral infections (URI) are a major cause of absence from school and work. Although morbidity is low in most of the subjects, the complications of URI, including otitis media, sinusitis and exacerbations of asthma and chronic obstructive pulmonary disease (COPD) have an enormous health impact. Despite the major health care consequences associated with these complications, our understanding of how URI trigger upper airway symptoms and cause exacerbations of lower airway diseases remains limited. This article reviews our current understanding of the pathogenesis of URI, and of viral exacerbations of asthma and COPD, and considers host defense parameters that may regulate susceptibility to disease exacerbations. We will also consider current and potential therapeutic approaches for the treatment of URI and their lower airway complications.